Low bioavailability of drugs after oral administration is considered to be caused by the following factors. (1) In oral administration of formulations such as common tablets and capsules, the concentration gradient of the drug between the digestive lumen and the blood increases immediately after release of the drug from the oral formulation, but rapidly decreases while the formulation moves to the lower part of the digestive tract, which gives a disadvantage to the drug absorption conditions. (2) Drugs such as furosemide are absorbed from the limited absorption site of the upper part of the small intestine (the so-called window effect), and common formulations of such drugs cannot exhibit satisfactory bioavailability after passing through the absorption site. (3) Drugs of protein or peptide are subjected to drastic hydrolytic degradation by digestive enzymes secreted to the digestive tract, whereby the bioavailability is reduced to only a few percentage. (4) HIV protease inhibitors such as ritonavir, saquinavir, indinavir and nelfinavir are, after absorbed from the digestive tract, actively excreted by excretory proteins such as P-gp expressed on the epithelial cell membrane of the intestinal tract.
In order to improve low bioavailability of drugs caused by the window effect, Akiyama et. al. developed mucosa adhesive granule formulations (Pharmaceutical Research, vol. 12, pp. 397–405, 1995).
As conventional techniques for improving bioavailability of protein and peptide after oral administration, with the main object of preventing hydrolytic degradation in the stomach and the small intestine, there have been developed a colon dissolvable azopolymer-coated insulin tablet by Dr. Saffran et. al., an emulsion preparation from Cortex Co., a technique for manufacturing oral formulation by Takada, a colon delivery technique, and a liposome preparation by Takada (Takada, Pharm. Tech. Japan, 1988, pp. 1299–1307; Takada, Pharm. Tech. Japan, 1991, pp. 512–52; Takada, Pharm. Tech. Japan, 1995, pp. 1335–1344; Ko et. al., Nippon Rinsho [Japan Clinicals], 1998, pp. 595–600) and the like.